Thrombosis From vitamin K antagonism to new oral : basic concepts

S. Schulman ABSTRACT Vitamin K antagonists have been used as oral anticoagulants since 1942, but the dose is difficult to Department of Medicine, McMaster predict beween individuals and is also variable over time in most patients. The research to produce University and Thrombosis and improved, target-specific anticoagulants started with the inhibitor in 1981. This Atherosclerosis Research Institute, was followed by several injectable thrombin and factor Xa inhibitors, but the ideal drug had to be oral - Hamilton, Canada and Karolinska ly available. It was necessary to map the catalytic site in order to understand how a highly selective Institutet, Stockholm, Sweden inhibitor can be developed. Structure-activity-relationship studies with a variety of analogs were cru - cial to identify compounds that combined potency, selectivity, membrane permeability and long half- Correspondence: life. These efforts from a dozen pharmaceutical companies have now resulted in one thrombin Sam Schulman inhibitor () and four factor Xa inhibitors (, , and ) E-mail: [email protected] that are either already used in clinical practice or in final stages of phase III clinical trials. These drugs are orally available and do not require routine laboratory monitoring due to a predictable therapeutic dose for the majority of patients. Additional advantages of these anticoagulants are rapid onset of Hematology Education: effect, faster decrease in effect after discontinuation than with , and a lower risk for intracra - the education program for the nial bleeding. They appear to have a higher risk of lower intestinal bleeding and there is to date no annual congress of the European widely available coagulation screening test that allows drug level to be assessed for all new agents Hematology Association and no clinically available reversal agent. This review describes the evolution of these new agents by 2014;8:383-390 focusing on basic concepts. Learning goals At the conclusion of this activity, participants should be able to: - understand the drug development process of oral anticoagulants; - describe the common features of the new oral anticoagulants; - describe potential benefits of the new anticoagulants based on their pharmacological characteristics.

Introduction atives have a very indirect effect by inhibiting a vitamin K reductase, which leads to decreased Vitamin K antagonists have been used for oral reduction of vitamin K 2,3-epoxide and in turn to a depletion of vitamin KH 2, and finally inadequate anticoagulation for 60 years and were initially dis - g covered in 1922. In that year, the Canadian veteri - -carboxylation of coagulation factors II, VII, IX narian Frank Schofield published in The Canadian and X, as well as of the coagulation inhibitors pro - Veterinary Record his observations on cattle with tein C and protein S and other ‘off target’ proteins a hemorrhagic disease and concluded that it was (Figure 1). This is, however, not the only reason caused by moldy sweet clover. 1 Subsequently, in for the difficulty in predicting the inter- and intra- 1938, the agricultural biochemist Karl Paul Link individual effect of warfarin over a period of time. and co-workers at the University of Wisconsin Various factors all contribute to the fact that the crystallized 6 mg of the substance daily dose can vary from 0.5 mg to 20 mg between from spoilt sweet clover and synthesized patients: i) two enantiomers that are metabolized dicumarol (3,3’-methylenebis-(4 hydroxy - by different microsomal enzymes; ii) interactions )). 2 In 1942, the prophylactic and thera - with food and a large number of drugs; iii) a high peutic effect of the drug was reported in three degree of plasma protein binding (>99%) with a independent publications by Allen, Butsch and very small free and active fraction; iv) gene poly - Lehman. 3-5 Link continued his laboratory work to morphisms that affect both the rate of drug metab - develop a more potent anticoagulant and in 1948 olism (Cytochrome P450 [CYP] 2C9) and the tar - produced warfarin, the first 4 letters of which get enzyme vitamin K epoxide reductase subunit stand for the Wisconsin Alumni Research 1 (VKOR C1 ); and v) general disturbances in liver Foundation. metabolism in congestive heart failure or from thyroid hormone. Characteristics of warfarin Consequences for management of war - Warfarin soon became the most frequent farin coumarin derivative used for oral anticoagulation worldwide and still remains so today. These deriv - The resulting variability in effect of warfarin Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) | 383 | 19 th Congress of the European Hematology Association

requires more intensive laboratory monitoring than for any plex with small peptides (D-Phe-Pro-Arg CH 2Cl) and non- other drug used long term. 6 In many countries, specific petidic molecules. Now the road was paved to design anticoagulation clinics have been organized to manage small molecules that would fit snugly into the serine pro - large numbers of these patients. Measurement of the pro - tease pocket. thrombin time is taken on average every 2-3 weeks. This incurs a burden for those patients who are working, but The prototypes also for the elderly who may be unable to visit the antico - agulation clinic or the medical laboratory. Investigation of the active site of thrombin revealed that It has, therefore, been a longstanding wish to design it contains 3 strategic pockets, the D-pocket, the P-pocket anticoagulant drugs that are orally administered but that and the S-pocket, with some alternative molecular compo - do not require laboratory monitoring. Attempts were made nents that will fit into the respective areas (Figure 1). The in the 1980s to develop such a drug. Thrombin, the last small molecules designed to fit into these pockets bind in the coagulation cascade, seemed to be reversibly, in contrast to or its analogs which bind an important specific target for anticoagulation therapy. irreversibly to the adjacent thrombin exosite 1 and in addi - With the availability of X-ray crystallography, Bode et al. tion block the active site. The reversible inhibition of the at the Max-Planck Institute for biochemistry were able to active site is, at least theoretically, an advantage that report the crystallographic 3-dimensional configuration of allows for some thrombin formation and reduced risk of the thrombin molecule reaching a resolution of 1.9Å. 7 This bleeding. Some pharmacokinetic characteristics of these revealed the configuration of the active site pocket in com - drugs are summarized in Table 1.

Table 1. Characteristics of 1st-generation small-molecule thrombin inhibitors.

Compound MW Ki Half-life Clearance Not orally available Argatroban 509 g/mol 40 nmol/L 20-60 min 4.4-5.8 mL/min/kg Efegatran 416 g/mol 18 nmol/L 35-150 min 5.9-6.4 mL/min/kg 439 g/mol 15 nmol/L 60 min 5.4 mL/min/kg Napsagatran 559 g/mol 3 nmol/L 40-124 min 5.5-6.6 mL/min/kg Orally available Melagatran 430 g/mol 2 nmol/L 150-260 min * Atecegatran 497 g/mol 2-4 nmol/L 9-14 h 13 mL/min/kg

MW: molecular weight; K i inhibition constant. *Clearance was correlated to creatinine clearance.

Figure 1. Schematic view of the catalytic site of thrombin with a putative direct thrombin inhibitor fitting in.

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The prototype synthetic thrombin inhibitor was arga - effect; in approximately 7% of patients this only manifest - troban (MD-805) from Daiichi Seyaku (Tokyo, Japan) 8 ed as transient elevation of liver transaminases, but in a and the only one of the 1st-generation agents that became few patients it also resulted in jaundice and fatal out - approved, and this is still used for anticoagulation in come. 16 This appears to be an idiosynchratic effect -induced thrombocytopenia. It is metabolized in depending on host immune response characteristics. the liver and is the only agent available for this condition was, therefore, withdrawn from all trials and in patients with severe renal failure. markets in 2006. Another of the first small molecule active site inhibitors The company, which now had become Astra-Zeneca, was efegatran GYKI-14766 (D-MePhe-Pro-Arg-H), continued with a 2nd-generation oral thrombin inhibitor, which was developed in Hungary and turned out to have a atecegatran (AZD0837), again a prodrug with the active 17 slow-tight binding. 9 It was evaluated in acute coronary metabolite AR-H067637. It has the same benzamidine syndromes and a had similar effect to unfractionated group as melagatran, fitting in the S-pocket, but this mol - 10,11 ecule did not appear to cause elevation of liver transami - heparin. 18,19 Inogatran, developed by Astra Hässle (Mölndal, nases. In two phase II studies in patients with atrial fib - Sweden) was a peptidomimetic substance intended for rillation, the drug appeared safe and effective. A slow eventual oral administration but evaluated as intravenous release preparation to enable once-daily administration infusion in patients with . 12 Inogatran was to be tested in phase III but was never started due to turned out to be inferior to heparin regarding episodes of lack of a sponsoring partner and increasing competition. ischemia and other clinical outcomes, at least in the short One additional oral thrombin inhibitor, sofigatran (MCC term. At Hoffmann-La Roche (Basel, Switzerland), the 977; Mitsubishi Tanabe Pharma, Osaka, Japan), with a petidomimetic agent napsagatran (Ro 46-6240) was devel - molecular weight of 484 d, was investigated in a phase II oped. It was evaluated in a phase II study in acute deep study in patients with deep vein thrombosis, but no data vein thrombosis and two dose levels of napsagatran had are available and the company is no longer active in this similar effect to unfractionated heparin. 13 What these syn - field. thetic thrombin inhibitors have in common is that they have very low bioavailablity and are thus unsuitable for Direct Factor Xa inhibitors: principles oral administration. The clearance is rapid via the hepato- biliary route and administration is, therefore, by necessity, The crystal structure of Factor Xa was deposited in as intravenous infusion. 1993. The crystallographic studies demonstrated two main interaction sub-pockets in the active site (Figure 2), S1 and Proceeding to oral availability S4, where S1 is the most important for binding substrates or inhibitors and plays the biggest role for determining 20 The development process for a sophisticated direct selectivity. Most inhibitors do not react with the S3 pock - thrombin (or Factor Xa) inhibitor is complex. Once the et and the small S2 pocket seems to define the specificity important binding pockets within the active site and the versus thrombin inhibition. The S4-sub-pocket consists of space between them have been identified, construction can a hydrophobic box, a cationic hole and a water site (H 2O start. A variety of peptidomimetic moieties may show trapped), all of which are ligands for binding. A typical good affinity to the respective pocket. From a large num - small-molecule direct Factor Xa inhibitor consists of 3 ber of possible compounds, one or a few are selected, domains: the P1-group (binding to S1), the central scaf - based on inhibitory potency and selectivity for the target fold, and the P4 group (binding to S4). The P1-group can be highly basic (benzamidine, naphthyl amidine, enzyme. Studies on structure-activity-relationship (SAR) amidinothiopene, amidinoindole etc.), moderately basic are performed with this limited number of candidates. (amino isoquinolines, azaindole), or neutral (methoxy Additional substitutions in the main ligand-binding benzoyl, chlorophenyl, chlorothiopene), and this will domains of the inhibitor may be attempted at this stage. influence potency, permeability and absorption. The scaf - Furthermore, the permeability of membranes or bioavail - fold can be flexible or rigid. Finally, the P4-group can be ability has to be acceptable, and the half-life has to be long methoxybenxene, pyridyl piperidine, phenyl enough to enable once or twice daily oral administration. sulphonamide, amidodiphenyl, methoxy naphthalene sul - At Astra Hässle (Mölndal, Sweden), the next steps were fonamide, benzyl sulfonylpiperidine, phenyl imidazoline taken by basing the structure on the thrombin substrate or amidobenzofuran. fibrinopeptide A and striving for a high association rate constant to achieve rapid thrombin inhibition. Melagatran was still suffering from poor gastrointestinal absorption. The Xa inhibitor prototypes This was improved with addtional ethyl- and hydroxyl groups resulting in the prodrug ximelagatran and a The componds described in this section reached clinical 14 bioavailability of 20%. Ximelagatran was evaluated in a studies but have been withdrawn or are not being devel - large trial program, including multiple studies in major oped further. Their characteristics are summarized in orthopedic surgery, and in two phase III trials in atrial fib - Table 2. rillation and in the treatment and secondary prophylaxis of Among the first direct Factor Xa inhibitors, i.e. acting venous thromboembolism. The effect of ximelagatran was without , was DU-9065a, developed by comparable to low molecular weight heparin (orthopedic Daiichi Sankyo (Tokyo, Japan). 21 It suffered from low surgery) and to warfarin (, venous throm - bioavailability and relatively poor selectivity, and was boembolism) with a trend to less bleeding. 15 only evaluated in pilot clinical studies in patients with sta - Unfortunately, phase III trials revealed a hepatotoxic ble coronary artery disease, 22 non-ST-elevation myocar -

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dial infarction, 23 and percutaneous coronary intervention. 24 drome (RUBY-1). It was effective in hip replacement to Although enteric coating seemed to improve bioavailabil - prevent thrombosis without compromising safety. 30 ity, 25 the development was stopped in favor of DU-176b RUBY-1 did not demonstrate any increase in efficacy by (now edoxaban). Another early direct Xa inhibitor that adding darexaban on top of dual antiplatelet therapy, but reached clinical trials was razaxaban (BMS-561389; the rate of bleeding increased 4-fold. 31 The development Bristol-Myers-Squibb, New York, NY, USA). From a was stopped in 2011, again due to lack of a partner and basic pyrazole Xa inhibitor, the P1-group was modified to increasing competition. aminobenzioxazole to improve selectivity and the P4-moi - Lilly (Indianapolis, IN, USA) introduced LY517717, ety was optimized to enhance permeability and reduce the which was evaluated in phase II in patients with knee or protein binding. 26 Razaxaban was evaluated in a phase II hip replacement surgery. The compound seemed effective study in knee replacement surgery but there was an with a low risk of bleeding. 32 Development ceased, how - increased risk of bleeding compared to low molecular ever, in 2005, possibly due to pre-clinical toxicity. weight heparin. 27 Development was stopped since the Eribaxaban (PD 0348292; Pfizer, New York, NY, USA) company already had another, more favorable candidate: is one of the most potent direct Factor Xa inhibitors. It was apixaban. studied in phase II trials in patients with knee replacement GW 813893 (Glaxo-Smith-Kline, Brentford, London, surgery with promising results. 33 The company decided, UK) was withdrawn after only phase I studies 28 and only however, not to continue the development of this drug limited information is available. when they joined forces with Bristol-Myers-Squibb to Darexaban (YM150; Astellas, Northbrook, IL, USA) develop apixaban. has a half-life of 18-20 h, allowing for once daily oral Letaxaban (TAK 442; Takeda, Osaka, Japan), yet anoth - administration. One of its metbolites is also active. 29 The er Factor Xa inhibitor with good bioavailability, 34 also drug was studied in phase II in patients with total hip showed promising efficacy and safety in a dose-finding replacement (ONYX-2) and with acute coronary syn - study in total knee replacement. 35 A phase II study in acute

Figure 2. Schematic view of the catalytic site of factor Xa with a direct Xa inhibitor prototype (DX 9065a) fitting in.

Table 2. Characteristics of 1st-generation small-molecule oral factor Xa inhibitors.

Compound MW Ki Half-life Bioavailability DX 9065a 571 g/mol 41 nmol/L 40-300 min 3% Razaxaban 528 g/mol 0.19 nmol/L 205 min 84% GW 813893 355 g/mol 7 nmol/L ? >55% Darexaban 475 g/mol 31 nmol/L 18-20 h 47% LY517717 460 g/mol 4.6-6.6 nmol/L 25 h 25-80% Eribaxaban 485 g/mol 0.32 nmol/L 10 h ? Letaxaban 480 g/mol 1.8 nmol/L 9-13 h 50%

MW: molecular weight; K i inhibition constant.

| 386 | Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) Milan, Italy, June 12-15, 2014 coronary syndromes has been completed but not published cates the concomitant use of only a couple of drugs, main - (clinicaltrial.gov identifier:00677053) . ly ketoconazole. For other P-gp substrates (verapamil, amiodarone), administration a few hours apart is sufficient to minimize the interaction. The 2nd-generation of new oral anticoagulants

The development of new oral anticoagulants is now well Dose predictability into the 2nd-generation and three of those have already been approved for one or several indications. These The most striking advantage of these new agents com - include one thrombin inhibitor (dabigatran) and two factor pared to warfarin is that one or sometimes two dose regi - Xa inhibitors (rivaroxaban and apixaban). In addition, the mens fit all patients and that the onset of effect is virtually Factor Xa inhibitors edoxaban and betrixaban are in immediate. From this, it follows that within hours of the advanced stages of clinical trials. Although efforts have first oral dose patients are effectively anticoagulated, in also been invested in drugs against other targets (Factors contrast with warfarin, which takes 5-7 days to reach ther - XII, XI, IX, VIII, VIIa) these candidates have either been apeutic effect, and in addition typically takes 3-4 more abandoned or are still in very early development and will weeks until a stable maintenance dose has been estab - not be discussed here. It is thus the coagulation factor- lished. For the new drugs, the same dose regimen can then enzymes in the common pathway (Factor Xa and IIa) that be continued year after year provided that renal function is are the focus of our interest. The topic of the optimal target normal or only mildly reduced. With warfarin, this phe - has been extensively discussed. Although there are several nomenon is seen in a minority of patients, 36 whereas the theoretical reasons why one or the other should be a better majority require dose adjustments every one or several target, evidence from the clinical trials indicates that phar - weeks for the reasons described above (see Characteristics macokinetics, and appropriate selection of dose and of of warfarin). There is still an open question as to whether indication for treatment are more important factors. outcomes with the new anticoagulants can be further Furthermore “beauty is in the eyes of the beholder”, and improved with some individual fine-tuning of the dose both physicians and patients may have different values regimen. and preferences, putting safety, efficacy, convenience or other factors at the top of their list of priorities. The characteristics of the five most clinically relevant Reversibility of effect new oral anticoagulants are summarized in Table 3. It is not the mandate of this review to discuss the results from The fact that the new oral anticoagulants bind reversibly clinical trials with these agents, and overall 170,000 to the catalytic site is sometimes confused with the patients have been included in the published trials provid - absence of agents to reverse their effect. It is, however, ing a wealth of clinical data. Instead, some common fea - clear that the half-life of these new agents is shorter (Table tures will be reviewed below. All these compounds bind 3) than that of warfarin (36-48 h). Unless the patient has reversibly to the catalytic site of the target. For all of them, slipped into severe renal failure, the anticoagulant effect there is some interaction with other drugs that are sub - will thus abate relatively fast once administration has been strates for the efflux transporter P-glycoprotein (perme - interrupted. The implications are that the new drugs ability glycoprotein; P-gp), which, in reality, contraindi - should be stopped with a shorter interval before surgery

Table 3. Characteristics of the current oral thrombin and Factor Xa inhibitors.

Characteristic Dabigatran Rivaroxaban Apixaban Edoxaban Betrixaban (BIBR 1048) (Bay 59-7939) (BMS-562247) (DU 176b) (PRT 054021; MLN-1021)

Drug/prodrug Prodrug (dabigatran etexilate) Drug Drug Drug Drug Target IIa (thrombin) Xa Xa Xa Xa Molecular weight 628 472 g/mol 436 g/mol 460 g/mol 720 548* g/mol 452 g/mol

Ki 4→.5 nmol/L 0.4 nmol/L 0.08 nmol/L 0→.56 nmol/L 0.12 nmol/L Bioavailability 6% Almost 100% for 10 mg, 50% 62% 34-47% less for higher doses

Time to maximum effect (t max ) 1.5-2 h 2 h 3-4 h 1-2 h 3-4 h Half-life (t½) 12-17 h 5-9 h* 8-15 h 9-10 h 20 h Plasma protein binding 35% 92-95% 87% 40-59% 80% Renal elimination of active drug 80% 33% 25% 35-39% <5% Interactions mediated by P-gp P-gp, CYP3A4 P-gp, CYP3A4 P-gp, (CYP3A4) P-gp Food effect Absorption delayed, Required for absorption Not reported No Absorption reduced 20% not reduced of doses >10 mg *The drug is administered as edoxaban tosylate (DU-176b) but is found in plasma as its free base edoxaban (DU 176).

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than the recommended five days for warfarin, 37 and that Conclusions despite the absence of antidotes, the risks in emergency 38 surgery or the outcomes of major bleeding complica - After more than 50 years with vitamin K antagonists as 39 tions are not worse than those in patients on warfarin. the only oral anticoagulants, a large number of highly spe - Hemodialysis can be used to remove drugs with low cific Factor IIa and Xa inhibitors have been developed dur - plasma protein binding (Table 3), as demonstrated for ing the past 15 years. This was made possible by the use of dabigatran. 40 X-ray crystallography to define the characteristics of the catalytic site and by advanced SAR techniques to optimize the inhibitors regarding selectivity, potency, permeability Assessment of effect and half-life. Still, approximately two-thirds of the new oral anticoagulants that entered into the clinical trial stage did Although the new anticoagulants are not intended for not make it all the way through. This was partly due to routine laboratory monitoring, situations may occur where unanticipated bleeding or other adverse events, but was also an assessment of the drug level is desirable (suspected a result of financial considerations. Five agents remain for overdose, major bleeding, emergency surgery, acute renal use in clinical practice or are ready to enter the market in the failure). So far, there is no single coagulation test that will next 1-2 years. The advantages have been demonstrated in be helpful regardless of the drug taken, partly because two multiple trials and include predictable clinical effect, few different targets are involved, but there is also a difference interactions, freedom from routine laboratory monitoring, between drugs in the same class for reasons that are still rapid onset of effect and faster disappearance of anticoagu - unclear. Prothrombin time gives a qualitative assessment lant effect after discontinuation than with warfarin, as well for rivaroxaban and edoxaban but not for apixaban or as lower risk for intracranial bleeding. Some disadvantages dabigatran. 41 The international normalized ratio (INR), are the lack of a single, widely available screening test to which is specifically intended for vitamin K antagonists, assess the plasma level of these new agents, the increased should not be used here. Activated partial thromboplastin risk of gastrointestinal bleeding and, for the time being, lack time and thrombin time will provide a rough qualitative of a clinically available reversal agent. From a strict clinical assessment for dabigatran. More specific analyses, that are point of view, the advantages seem to outweigh the draw - backs. for the moment only available at major hospitals, and usu - ally not on an emergency basis, can give a quantitative measurement of the activity and be translated into plasma References concentration of dabigatran (dilute thrombin time, Hemoclot, anti-factor IIa methods) or the Xa inhibitors 1. Schofield FW. A brief account of a disease in cattle simulating 41 hemorrhagic septicaemia due to feeding sweet clover. Can Vet (anti-Factor Xa assays). Rec. 1922;3:74-8. 2. Link KP. The anticoagulant from spoiled sweet clover hay. Harvey Lect. 1943-44;39:162-216. 3. Allen EV, Barker NW, Waugh JM. A preparation from spoiled sweet clover (3,3’-methylene-bis- (4-hydroxycoumarin)) Specific safety benefit which prolongs coagulation and prothrombin time of the blood: a clinical study. JAMA. 1942;120:1009-15. It is evident from all the phase III trials in atrial fibrilla - 4. Butsch WC, Stewart JD. Clinical experiences with dicoumarin, 3,3’-methylene-bis-(4-hydroxycoumarin). tion, with the same patterns seen in the treatment of JAMA. 1942;120:10256. venous thromboembolism, that the new anticoagulants are 5. Lehmann J. Hypoprothrombinaemia produced by methylene- associated with a lower risk for intracranial bleeding than bis- (hydroxycoumarin), its use in thrombosis. Lancet. 42 1942;1:318. warfarin. It was initially thought that this is a result of 6. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti more predictable drug levels with a much lower risk for G. 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